Dumont E, Fuchs K P, Bommer G, Christoph B, Kremmer E, Kempkes B
Institut für Klinische Molekularbiologie und Tumorgenetik, GSF-Forschungszentrum für Umwelt und Gesundheit, München, Germany.
Oncogene. 2000 Jan 27;19(4):556-61. doi: 10.1038/sj.onc.1203352.
Signalling through the transmembrane receptor Notch is triggered by ligand binding, which induces the proteolytic cleavage of the Notch protein. This cleavage generates an intracellular fragment of the Notch protein (Notch-IC), which translocates into the nucleus and modifies transcription of target genes through its association with the RBP-J protein. Thus, the isolated Notch-IC protein represents the constitutively activated receptor. We have performed a deletion analysis of Notch IC in order to identify the transferable transactivation domain of Notch-IC and the minimal domain of Notch-IC required for RBP-J dependent transactivational activation. Functionally, Notch-IC has been linked to cell fate decision in development and oncogenesis in vivo. In vitro, Notch-IC can cooperate in neoplastic transformation of baby rat kidney cells with the adenoviral E1A protein. We have defined the minimal domain of Notch-IC required for E1A cotransformation. This domain, consisting of the ankyrin repeats of Notch-IC only, can neither activate RBP-J dependent transcription nor does it carry a transactivation domain. Therefore, the ankyrin repeat domain of Notch-IC might trigger novel pathways relevant for transformation but unrelated to RBP-J signalling.
通过跨膜受体Notch的信号传导由配体结合触发，这会诱导Notch蛋白的蛋白水解切割。这种切割产生Notch蛋白的细胞内片段（Notch-IC），它会转运到细胞核中，并通过与RBP-J蛋白结合来修饰靶基因的转录。因此，分离出的Notch-IC蛋白代表组成型激活受体。我们对Notch IC进行了缺失分析，以确定Notch-IC的可转移反式激活结构域以及RBP-J依赖性反式激活所需的Notch-IC最小结构域。在功能上，Notch-IC与体内发育和肿瘤发生中的细胞命运决定有关。在体外，Notch-IC可以与腺病毒E1A蛋白协同作用，促进幼鼠肾细胞的肿瘤转化。我们已经确定了E1A共转化所需的Notch-IC最小结构域。该结构域仅由Notch-IC的锚蛋白重复序列组成，既不能激活RBP-J依赖性转录，也不携带反式激活结构域。因此，Notch-IC的锚蛋白重复结构域可能会触发与转化相关但与RBP-J信号传导无关的新途径。
